Thieno-(2,3-e)(1,4)diazepin-2-ones

ABSTRACT

1. THIENO-(2,3-E)(1,4) DIAZEPIN-2-ONES OF THE FORMULA-   1-R2,2-(O=),5-(2-HAL-PHENYL-),7-R1-THIENO-(2,3-E)(1,4)-   DIAZEPININE   WHEREIN R1 IS A LOWER ALKYL GROUP OF FROM 1 TO 2 CARBON ATOMS; R2 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF A HYDROGEN ATOM AND A METHYL GROUP; AND HAL REPRESENTS A HALOGEN ATOM; AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF.

United States Patent Olfice US. Cl. 260239.3 B Claims ABSTRACT OF THEDISCLOSURE Thieno-[2,3-e][1,4Jdiazepin-2-ones of the formula:

wherein each of R and R is a member selected from the group consistingof H and a lower alkyl group of from 1 to 4 carbon atoms, and wherein Rand R may also combine to form a member selected from the groupconsisting of trimethylene and pentamethylene; R is a member selectedfrom the group consisting of H and a lower alkyl group of from 1 to 4carbon atoms; and R is a member selected from the group consisting of H,a halogen atom, CF and a lower alkoxy group of from 1 to 4 carbon atoms,providing that R does not represent H when each of R and R is a memberselected from the group consisting of H and a lower alkyl group of from1 to 4 carbon atoms; and the pharmaceutically acceptable acid additionsalts thereof, and process for preparing same.

The compounds encompassed by the above formula exhibit pharmacologicalactivity in narcosis potentiation, suppression of fighting behaviour andanti-convulsant activity.

SUMMARY OF THE INVENTION The present invention relates to novel andtherapeutically valuable thieno-[2,3-e][l,4]diazepin-2-ones of theformula:

CHa 0:4)

3,849,405 Patented Nov. 19, 1974 bon atoms, providing that R does notrepresent H when each of R and R is H or a lower alkyl group of from 1to 4 carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION The compounds (I) can be producedby the following methods:

(i) By condensation of a compound of the formula:

R -Q R1 ,1 u

N(R )C0CHzN2 (II) or a salt thereof such as hydrobromide orhydrochloride, wherein R, R R and R are as defined above.

The reaction is usually carried out in a solvent such as benzene,toluene, xylene, chloroform, tetrahydrofuran, dimethylformamide orpyridine, at an elevated temperature and preferably at refluxingtemperature. It is also preferred that the water formed be continuouslyremoved azeotropically.

(ii) -By reaction of a compound of the formula:

S N(R3) COCHiNa (III) XS NHR IV with a compound of the formula H NCHCOOR (V) or a salt thereof such as hydrochloride, wherein R is a loweralkyl group and R, R R and R are as defined above.

Thereaction is usually carried out in a solvent such as benzene,toluene, chloroform, tetrahydrofuran, dimethylformamide or pyridine atan elevated temperature, preferably at refluxing temperature, preferablythe water or 'alkanol formed being removed continuously.

The compounds (I) Where R is a lower alkyl group are also produced bythe following method:

(iv) By reaction of a compound of the formula:

wherein X is a reactive atom or group (e.g., halogen, methylsufonyloxy,p-tolylsulfonyloxy or sulfuric acid residue) and R, R R and R are asdefined above.

The reaction is usually carried out in a solvent first by converting acompound (1) into an alkali metal salt with a metalating agent, such asan alkali metal (Li, Na or K) or an alkali metal compound (hydride,alkoxide or amide of an alkali metal), and then reacting the alkalimetal salt with compound (VI), at a temperature of from room temperatureto refluxing temperature. The solvent employed is, for example,methanol, ethanol, benzene, Xylene, tetrahydrofuran ordimethylformamide.

The starting compounds (II) and (III) are new compounds and can beproduced, for example, by the following methods:

CICHZCOCJ. C1C0CH NllCCIl 2 I i R s N (a COCHZCJ.

2 3 R 5 NH! )COCI-I NH-COOCH o R erg t a e 1 1 (II) 2 I I 3 R s N(R)cocu N (III) Specific examples of the preparation of starting compounds(II) and (III) are as follows:

(1) Preparation of Starting Compounds (III) (a) To a solution of 8.5 g.of 2-amino-3-benzoyl-5,6- dihydro-4H-[l]cyclopentathiophene in 100 ml.of chloroform is added, under ice cooling, 8.3 g. ofN-benzyloxycarbonylglycyl chloride, and the resulting mixture is allowedto stand in an icebox overnight. The solvent is distilled off and thecrude crystals thus obtained are recrystallized from ethanol to givepale yellow crystalline 2-benzyloxycarbonylacetamido-3-benzoyl 5,6dihydro- 4H[l]cyclopentathiophene, melting at 114-115 C., in yield.

To 12 g. of benzyloxycarbonylacetamido-3-benzoyl-5,6-dihydro-4H-[l]cyclopentathiophene is added 30 ml. of a 20% solution ofhydrogen bromide in acetic acid. The resulting mixture is stirred atroom temperature, and 200 ml. of isopropyl ether is added. The crystalsthus obtained are collected by filtration, washed with three 50 ml.portions of isopropyl ether, and 50 ml. of water is added. The aqueoussolution is made alkaline with sodium hydrogen carbonate and extractedwith chloroform. The extract is dried over sodium sulfate, the solventis distilled olf, and the crude crystals thus obtained arerecrystallized from ethanol to give pale yellow crystalline 2-aminoacetamido 3 benzoyl-5,6-dihydro-4H-[1]cyclopentathiophene, meltingat l30l31 C., in 79% yield.

(b) Ammonia gas is introduced under ice cooling to a solution of 20 g.of 2-iodoacetamido-3-o-chlorobenzoyl- S-ethylthiophene in 50 ml. ofdichloromethane and 5 ml. of methanol. After the introduction of ammoniagas for 2 hours, the solution is stirred at room temperature for 2 hoursto complete the reaction. The reaction mixture is Washed with ice waterand then with a saturated sodium hydrogen carbonate solution, dried oversodium sulfate, and concentrated under reduced pressure. Thecrystallization takes place on adding ethanol to the residue. Thecrystals are collected by filtration and washed with a small amount ofethanol to give 11.7 g. of almost pure2-aminoacetamido-3-o-chlorobenzoyl-5-ethylthiophene, melting at 146-148"C.

(c) 2-azidoacetamido-3-o-chlorobenzoyl 5 ethylthiophene (5 g.) is addedto 50 ml. of a 30% solution of hydrogen bromide in acetic acid, and theresulting mixture is shaken at room temperature for 1 hour. After theevolution of nitrogen gas ceases, isopropyl ether is added to thereaction mixture. The orange-colored gelatin-like substance thusprecipitated is collected by decantation, isopropyl ether is addedagain, and the mixture is mixed well. The substance graduallysolidifies. The solid is collected by filtration, washed several timeswith isopropyl ether, and dissolved in 50 ml. of chloroform. 5 g. oftriethylamine is added, the resulting solution is allowed to stand atroom temperature for 2 hours, washed with water and dried over magnesiumsulfate. The chloroform is distilled off under reduced pressure to givewhite crystalline 2 aminoacetamido-3-o-chlorobenzoyl 5 ethylthiophene.melting at 146-148 C. (from ethanol).

(2) Preparation of Starting Compound (IH) To a solution of 2.5 g. of2-iodoacetamido-3-o-methoxybenzoyl-S-ethylthiophene in 15 m1. ofdimethylformamide is added, with stirring, 0.42 g. of sodium azide, andthe resulting mixture is stirred at 60 C. for 30 minutes. After thereaction, 20 ml. of ice water is added dropwise to the reaction mixtureand the entire mixture is cooled to room temperature. The red-browngelatin-like substance thus obtained is treated with ligroin to givewhite crystalline 2- azidoacetamido-3-o-methoxybenzoyl 5 ethylthiophene.melting at 8384 C.

The compounds of formula (I) can be converted into the correspondingacid addition salts in a conventional manner by treatment with variousinorganic and organic acids, for example, hydrochloric, hydrobromic,nitric, sulfuric, phosphoric, p-toluenesulfonic, citric, maleic,fumaric, succinic, formic, acetic and tartaric acid.

The compound of formula (I) and pharmaceutically acceptable acidaddition salts thereof have excellent pharmacological activities innarcosis potentiation, suppression of fighting behavior andanticonvulsant effect as shown, for example, by the following tests.

(I) Narcosis Potentiation (II) Suppression of Fighting Behavior Fightingepoxides were produced in mice by the method described by Tedeschi etal. in The Journal of Pharmacology and Experimental Therapeutics, Vol.125, p. 28 if. (1959). Eight groups of 8 female mice (4 pairs) weregiven the test compound orally 60 minutes prior to receiving an electricfoot-shock for 3 minutes with 530 volts J interrupted direct current,1.3 milliamperes, 10 cycles per second. Those exhibiting 3 fightingepisodes or less within 3 minutes were deemed to be suppressed by thetest compound. The control mice (81 pairs) had shown the fightingepisodes of 8.7 times on the average under the same conditions. The'EDthe dose required to suppress 50% of fighting pairs, was determinedgraphically.

(III) Anticonvulsant Effect Pentylenetetrazol (150 mg./kg.) wasadministered subcutaneously to eight groups each consisting of 6 mice,minutes after the intraperitoneal administration of the test compound.The number of dead mice were counted within 3 hours after theadministration of pentylenetetrazol, and then the ED the dose requiredto suppress the lethal rate to 50%, was determined graphically.

[2,3-e] [l,4]diazepin-2-one- B: 5 ochlorophenyl-7-ethyl-1-methyl-1,2-dihydro-3H- thieno- [2,3-e] 1,4]diazepin-Z-one C: 5 o chlorophenyl-7-methyl-1,2-dihydro-3H-thieno-[2,3-e] [1,4] diazepin-Z-one D: 5 o chlorophenyl1,7-dimethyl-1,2-dihydro-3H- thieno- [2,3-e] 1,4] diazepin-Z-one In viewof the various tests including those mentioned above, the compounds ofthe invention represented by formula (I) and their pharmaceuticallyacceptable acid addition salts thereof can be administered safely asminor tranquilizers for the treatment of neurosis, anxiety, tension anddepressive states, in the form of a pharmaceutical preparation with asuitable and conventional carrier or adjuvant, administered orally,without harm to the patients.

The pharmaceutical preparations can take any conventional form such astablets, capsules or powders.

Formulation Example 5 mg. and 10 mg. tablets are prepared from thefollowing compositions:

5 mg 10 mg.

tablet tablet Compound (1), mg 5.0 10. 0 Lactose, mg 62. 3 57. 3 Cornstarch, mg 25.0 25. 0 Microcrystalline cellulose, mg 6.0 6. 0 Methylcellulose, mg 1. 0 1. 0 Magnesium stearate, mg 0. 7 0. 7

Total, mg 100.0 100. 0

1% and 10% powders are prepared from the following compositions powderpowder Compound (I), percent 1.0 10. 0 Lactose, percent 88.0 79. 0Mieroerystalline cellulose, percent 10.0 10. 0 Methyl cellulose,percent 1. 0 1. 0

Total 100. 0 100. 0

EXAMPLE 1 A solution of 7.5 g. of 2 aminoacetamido-3-benzoyl-5,6-dihydro 4H [1]cyclopentathiophene in 50 ml. of pyridine, 1.5 g. ofacetic acid and 15 ml. of benzene is refluxed for 3 hours in a flaskprovided with a waterremoving adaptor. The solvent is distilled off,water is added to the residue, the solution is made alkaline with sodiumhydrogen carbonate and extracted with chloroform. The chloroform layeris dried over sodium sulfate, the chloroform is distilled off, and thecrude crystals thus obtained are recrystallized from ethanol to givepale yellow crystalline 5 phenyl 1,2,7,8 tetrahydro-3H,6H[1]cyclopentathieno [2,3-e] [1,4]diazepin 2 one, melting at 243 C. withdecomposition, in 73% yield.

EXAMPLE 2 To a solution of 10 g. of2-aminoacetamido-3-o-chlorobenzoyl-S-ethylthiophene in 50 ml. ofpyridine are added 20 ml. of benzene and 1.9 g. of acetic acid. Theresulting mixture is refluxed with stirring for 10 hours in a flaskprovided with a water-removing adaptor. The reaction mixture isconcentrated, and the residue is extracted with chloroform. Thechloroform layer is washed with water and then with a sodium hydrogencarbonate solution, dried over magnesium sulfate. The chloroform isdistilled oif under reduced pressure, and toluene is added to theresidue. Thus is precipitated white crystalline 5-o chlorophenyl 7 ethyl1,2 dihydro-3H-thieno[1,3-e]- [1,4]diazepin 2 one, melting at 204-206 C.(from a mixture of toluene and ethanol).

EXAMPLE 3 To a solution of 4 g. of 2 azidoacetamido 3-0- methoxybenzoyl5 ethylthiophene in 60 ml. of ethanol are added 2 g. of 5% palladiumcharcoal and then a solution of 0.3 g. of hydrazine hydrate in 10 ml. ofethanol with stirring. The resulting mixture is stirred at roomtemperature for 2 hours (nitrogen gas develops vigorously) and then at50 C. for further 30 minutes. The insoluble catalyst is then filteredoff, and the filtrate is concentrated under reduced pressure. The oilyresidue is crystallized 7 from hexane to give pale yellow crystalline-o-methoxyphenyl 7 ethyl 1,2-dihydro-3H-thieno-[2,3-e][1,41diazepin-2-one, melting at l68l69 C. (from a mixture of ethanol andhexane).

EXAMPLE 4 To a solution of 8.3 g. of 2-amino-3-o-chlorobenzoyl-S-ethylthiophene in 40 ml. of pyridine is added 13 g. of ethyl glycinatehydrochloride, and the resulting mixture is refluxed with stirring for20 hours. The pyridine is then distilled off under reduced pressure, andthe residue is extacted with chloroform. The chloroform layer is washedwell with water and dried over magnesium sulfate, and the chloroform isdistilled off under reduced pressure. The red-brown oily residue ispurified by silica gel-chromatography using chloroform as developingsolvent. After removal of the first fraction containing the unreactedstarting material, the chloroform eluate containing the object compoundis concentrated under reduced pressure, and the residue is treated withtoluene to give white crystalline 5 o chlorophenyl 7ethyl-1,2-dihydro-3H-thieno- [2,3-e][1,4]diazepin 2 one melting at204206 C. (from a mixture of toluene and ethanol).

EXAMPLE 5 5 p chlorophenyl 6,7 dimethyl-1,2-dihydro-3H- thieno[2,3-e][l,4]diazepin 2 one (3.0 g.) is suspended in 70 ml. of toluene.The suspension is heated to 40 C. whereupon 0.58 g. of sodium methoxideis added, and the mixture is refluxed to make a homogeneous pale brownsolution. After about ml. of the methanol and toluene are distilled off,1.3 g. of dimethyl sulfate is added slowly, and the resulting mixture isrefluxed for 1 hour. After cooling, the toluene layer is washed withwater, then with a sodium hydrogen carbonate solution, dried over sodiumsulfate, and the toluene is distilled off. To the oily residue are addedhexane and a small amount of ethanol. Crystallization takes place whenthe flask is scratched. The crystals are collected by suction filtrationand recrystallized from a mixture of hexane and ethanol to give whitecrystalline 5 p chlorophenyl 1,6,7-trimethyl 1,2 dihydro 3H thieno[2,3-e] [1,4]diazepin- 2-one, melting at 182-184 C., in 76% yield.

Using the procedures set forth in the above examples, but substitutingequivalent amounts of the appropriate starting materials, the followingcompounds are also produced:

(1) 5 p chlorophenyl 6,7-dimethyl-1,2-dihydro-3H- thieno [2,3-e][1,'4]diazepin 2 one, melting at 243- 245 C., and its hydrobromide,melting at 262263 C.

(2) 5 m trifluoromethylphenyl 6,7,dimethyl-1,2-dihydro 3H thieno [2,3-e][1,4]diazepin-2-one, melting at 220222 C.

(3) 5 o chlorophenyl 7 isopropyl-1,2-dihydro-3H-thieno-[2,3-e][1,4]diazepin 2 one, melting at 243- 246 C.

(4) 5 o chlorophenyl 7 methyl-1,2-dihydro-3H- thieno[2,3-e][l,4]diazepin-2-one, melting at 212 213 C.

(5) 5 o chlorophenyl 7 ethyl-1-methyl-1,2-dihydro- 3H thieno[2,3-e][1,4]diazepin-2-one, melting at =105106 C. Y

(6) 5 phenyl 1,2,7,8,9',10 hexahydro 3H,6H [1] cycloheptathieno[2,3-e][1,4]diazepin-2-one, melting at 228-229 C.

8 r (7) 5 phenyl 1 methyl 1,2,7,8,9,10 hexahydro- 3H,6H[1]cycloheptathieno [2,3-e][1,4]diazepin2- one, melting at -151" C.

Although the present invention has been adequately described in theforegoing specification and examples included therein, it is readilyapparent that various changes and modifications may be made withoutdeparting from the scope and spirit thereof.

What is claimed is: V

1. Thieno-[2,3-e] [l,4]diazepin-2-ones of the formula:

Hal

wherein R is a lower alkyl group of from 1 to 2 carbon atoms; R is amember selected from the group consisting of a hydrogen atom and amethyl group; and Hal represents a halogen atom; and thepharmaceutically acceptable acid addition salts thereof.

2. The compound of Claim 1: 5 o chlorophenyl-7- ethyl 1,2 dihydro 3Hthieno [2,3-e][1,4]diazepin-Z-one.

3. The compound of Claim 1: 5 o chlorophenyl-7- ethyl 1 methyl 1,2dihydro 3H-thieno-[2,3-e]- [1,4]diazepin-2-one.

4. Th compound of Claim 1: 5 o chlorophenyl-7- methyl 1,2 dihydro 3Hthieno [2,3-e][1,4]diazepin-2-one.

5. The compound of Claim 1: 5 o chlorophenyl- 1,7 dimethyl 1,2 dihydro3H thieno [2,3-e] [1,4] diazepin-Z-one.

References Cited UNITED STATES PATENTS 3,558,606 1/1971 Tinney 260-23933,557,095 1/l971 De Wald 26023 9.3 B 3,558,605 1/1971 De Wald et al.260239.3 B 3,660,425 5/1972 De Wald et al. 260239.3 B 3,669,959 6/1972Hromatka et al. 260239.3 B

' OTHER REFERENCES Some Aspects of Structure-Activity Relationship inPsychotropic Agents of the 1,4-benzodiazepin-Series (Sternbach andRandall, a symposium held at the regional research laboratory, Hyderbad,India, CSIR, New Delhi, India (1966)).

Zbinden et al.: Pharmacology of Benzodiazepines from Advances inPharmacology vol. 5, pp. 250-261 (1967) (Academic).

HENRY R. JILES, Primary Examiner A R. T. BOND, Assistant Examiner US.Cl. X.R. 260332.2 R, 332.3 R; 424-244, 275

1. THIENO-(2,3-E)(1,4) DIAZEPIN-2-ONES OF THE FORMULA-